A mechanism accounting for the low cellular level of linoleic acid in cystic fibrosis and its reversal by DHA

M Rabie Al-Turkmani,Charlotte Andersson,Ragheed Alturkmani,Waddah Katrangi,Joanne E Cluette-Brown,Steven D Freedman,Michael Laposata

doi:10.1194/jlr.m800035-jlr200

Abstract

Specific fatty acid alterations have been described in the blood and tissues of cystic fibrosis (CF) patients. The principal alterations include decreased levels of linoleic acid (LA) and docosahexaenoic acid (DHA). We investigated the potential mechanisms of these alterations by studying the cellular uptake of LA and DHA, their distribution among lipid classes, and the metabolism of LA in a human bronchial epithelial cell model of CF. CF (antisense) cells demonstrated decreased levels of LA and DHA compared with wild type (WT, sense) cells expressing normal CFTR. Cellular uptake of LA and DHA was higher in CF cells compared with WT cells at 1 h and 4 h. Subsequent incorporation of LA and DHA into most lipid classes and individual phospholipids was also increased in CF cells. The metabolic conversion of LA to n-6 metabolites, including 18:3n-6 and arachidonic acid, was upregulated in CF cells, indicating increased flux through the n-6 pathway. Supplementing CF cells with DHA inhibited the production of LA metabolites and corrected the n-6 fatty acid defect. In conclusion, the evidence suggests that low LA level in cultured CF cells is due to its increased metabolism, and this increased LA metabolism is corrected by DHA supplementation.

Highlights

Specific fatty acid alterations have been described in the blood and tissues of cystic fibrosis (CF) patients
One hypothesis is that the low linoleic acid (LA) and docosahexaenoic acid (DHA) levels in CF cells are due to a selective decrease in one specific lipid compartment
We examined the cellular uptake of LA and DHA, their incorporation into lipid classes, and the metabolism of LA in cultured airway cells expressing the CF phenotype

Summary

Introduction

Specific fatty acid alterations have been described in the blood and tissues of cystic fibrosis (CF) patients. The other consistent fatty acid alteration (decreased DHA levels) was described in the blood and tissues of CF patients [11,12,13,14]. Other reported fatty acid abnormalities in CF include increased palmitoleic acid (16:1n-7) and eicosatrienoic acid (20:3n-9) in the plasma of CF patients [6, 13, 15, 16] In addition to these fatty acid alterations, increased arachidonic acid (AA) release from CF lymphocytes and from epithelial cell lines carrying the DF508 CFTR mutation has been described [17, 18]

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